Venous thromboembolism (VTE) VTE is the 3 rd most frequent CV - PowerPoint PPT Presentation

4/14/2016 Venous thromboembolism (VTE) • VTE is the 3 rd most frequent CV disease • 1 case per 1000 person-years Can Biomarkers Help to Guide • Most frequent site is DVT in the legs Duration of Therapy After VTE? • 1/3 of patients suffering from a 1 st episode of Marlene Grenon, MD VTE develop recurrence within 10 years Associate Professor of Surgery • Management options are changing: University of California San Francisco – LMWH-> Vit K antagonist direct oral anticoagulants UCSF Vascular Surgery Symposium 2016 Abuldstrom et al, Heart 2003; Ferreieres et al, Am J Cardiol 1995; Ellkjaer et al, Stroke 1997; Kyrle et al, Lancet 2005; Naess et al, J Thromb Haemost 2007; Shulman et al, J Thromb Haemost 2006. How Long to Treat with New Chest Guidelines 2016 Anticoagulants? • VTE (proximal DVT or PE) provoked by surgery: • Non-vitamin K antagonist oral anticoagulants – Recommend 3 months (NOACs) are suggested over warfarin for • VTE (proximal DVT or PE) provoked by non-surgical initial and long-term treatment of VTE in transient risk factor (e.g. estrogens, pregnancy, leg patients without cancer. injury, flight > 8 hrs): – Suggest 3 months – Since publication of the 9th edition, new studies • Unprovoked VTE (proximal DVT or PE): show that NOACs are as effective as VKA therapy – Suggest at least 3 months, then reevaluate for with reduced risk of bleeding and increased risk/benefit convenience for patients and health-care • Recurrent VTE providers. – Suggest extended treatment (no stop date) over 3 months ***consider bleeding risk in decision Chest 2016 1

4/14/2016 D-Dimers Can Biomarkers Aid in • Fibrin degradation Deciding on the Treatment Duration? product – Small protein fragment Decrease risk of VTE recurrence present in the blood Decrease risk of bleeding from anticoagulation after clot degraded by fibrinolysis D-Dimers • Name because it Endogenous Thrombin potential contains two P-Selectin crosslinked D fragments CRP and other inflammatory markers of the fibrin protein Clotting Factor VIII D-Dimers PROLONG TRIAL: Palareti et al, NEJM 2006 • For diagnosis of DVT • 608 patients with first unprovoked DVT – Sensitivity 96% • D-dimer testing 1 month after the discontinuation of – …but low specificity (40%) and PPV (48%) anticoagulation. – Normal d-dimer level -> not resume anticoagulation • Associated with an increased risk of recurrent – Abnormal d-dimer level -> randomly assigned either to VTE resume or to D/C tx – ** testing for antiphospholipid antibody + antithrombin – Relative risk 2.19 , 95% CI 1.10-4.35 deficiency-> if positive: excluded from further analysis – At 2 years: <250 ng/ml (3.7%) vs > 250 ng/ml • Study outcome: – composite of recurrent venous thromboembolism and (11.5%) major bleeding • Average follow-up of 1.4 years Rectenwald et al, Thromb Haemost 2005; Wakefiled et al, Art Thromb Vasc Biol 2008 2

4/14/2016 PROLONG TRIAL: Palareti et al, NEJM 2006 PROLONG TRIAL: Palareti et al, NEJM 2006 Patients with an abnormal d-dimer level 1 month after the discontinuation of anticoagulation have a significant incidence of recurrent venous thromboembolism, which is reduced by the resumption of anticoagulation. Recurrence of DVT- Vienna Prediction Model PROLONG TRIAL: Palareti et al, NEJM 2006 30% risk of recurrence over 10 years Patients with an abnormal d-dimer level 1 month after the discontinuation of D-Dimers may be useful in guiding the decision on duration anticoagulation have a significant incidence of recurrent venous of oral anticoagulation for secondary VTE prophylaxis thromboembolism, which is reduced by the resumption of anticoagulation. Eichinger et al, Vasc Med 2010 3

4/14/2016 Recurrence of DVT- Recurrence of DVT- Vienna Prediction Model Vienna Prediction Model Eichinger et al, Vasc Med 2010 Eichinger et al, Vasc Med 2010 Endogenous Thrombin Potential • Thrombin generation test – thrombin potential – endogenous thrombin potential • Information about the catalyst of the main reaction – transformation of fibrinogen into fibrin The “ man hours ” of thrombin activity • Calculates free thrombin The power of thrombin = generation = HC Beguin, CRIM, Netherlands The area Under the TG-curve = Endogenous Thrombin Potential (ETP) 4

4/14/2016 P-Selectin • Member of selectin family of cell adhesion molecules, stored in the alpha granules of platelets and Weibel- Palade bodies of ECs • P-Selectin receptor (PSGL-1) expressed in platelets and mediates platelet- endothelium interaction, fibrin formation and thrombus growth • Important molecule in hemostasis and thrombosis P-Selectin P-Selectin • Elevated in acute DVT and recurrent DVT • Elevated in acute DVT and recurrent DVT • LETS Study (Leiden Thrombophilia Study) • LETS Study (Leiden Thrombophilia Study) – Elevated sP-Selectin 6 months after DVT – Elevated sP-Selectin 6 months after DVT compared to controls ( odds ratio 2.1 , CI 1.2-3.6) compared to controls (odds ratio 2.1, CI 1.2-3.6) P-Selectin reflects a pro-thrombotic state but clinical applicability of measurements need to be standardized and investigated in interventional trials. Blann et al, Vr J Haem 2000; Ay et al, Clin Chem 2007; Kyrle et al, Thromb Hemo 2007 5

4/14/2016 Inflammatory cytokines: CRP Inflammatory cytokines: Others • Small amount of studies • IL 1-B, IL6, IL8, IL10, IL 12p70, TNF CRP: sensitivity 77% specificity 66% Reviewed in Fox et al, Thromb Hemo 2005 and Pabinger et al, Art Reviewed in Fox et al, Thromb Hemo 2005 and Pabinger et al, Art Thromb Vasc Biol 2009 Thromb Vasc Biol 2009 Inflammatory cytokines: Others Clotting Factor VIII + Other • IL 1-B, IL6, IL8, IL10, IL 12p70, TNF • Clotting Factor VIII: – Small number of studies – Genetically determined • ABO blood group system – May be predictor BUT interventional trials needed • Other biomarkers also needing further investigations: – E-Selectin – Micro-Particles Increased inflammatory cytokines may not constitute an independent risk marker for future VTE- Reviewed in Fox et al, Thromb Hemo 2005 and Pabinger et al, Art Thromb Vasc Biol 2009 further research needed 6

4/14/2016 Conclusion • Can Biomarkers Help to Guide Duration of Therapy After VTE? YES – Ongoing data support the use of biomarkers to predict recurrence risk + guide length/modality of treatment – Most promising: D-Dimers, ETP – More data needed: P-Selectin, E-Selectin, Micro- Particles Updated Vienna Model – time prediction 7